PDHB

protein-coding

pyruvate dehydrogenase E1 subunit beta, the group of Pyruvate dehydrogenase complex

Gene summary

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and carbon dioxide, and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 beta subunit. Mutations in this gene are associated with pyruvate dehydrogenase E1-beta deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2012]

MANE transcript

NM_000925.4

Inheritance

ClinVar variants

P:48U:95B:140

Top phenotype

Pyruvate dehydrogensae E1-beta deficiency

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr3:58,427,630-58,433,857

External References & Databases

Ensembl (ENSG00000168291)

Transcript & Mutation Effects

hg38 • Region Span ~6.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pyruvate dehydrogenase E1-beta deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013580

Submitter: Labcorp Genetics (formerly Invitae)

pyruvate dehydrogenase E1-beta deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013580

Submitter: Natera

pyruvate dehydrogenase E1-beta deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013580

Submitter: Genomics England PanelApp

pyruvate dehydrogenase E1-beta deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013580

Submitter: Ambry Genetics

pyruvate dehydrogenase E1-beta deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013580

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between PDHB and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2020. The PDHB gene encodes the E1 beta subunit of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, thus is the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. The PDHB gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2009 (PMID: 19924563). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants identified in seven cases in two publications (PMIDs: 21914562, 19924563). Of note, those with PDHB deficiency can also have structural brain abnormalities (corpus callosum abnormalities) and microcephaly. In addition, several affected individuals have neonatal lactic acidosis, raising the possibility that some affected individuals die before they would have developed Leigh syndrome spectrum. No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, and animal models (PMIDs: 27977873, 25613900, 25356417, 29501567, 31127358). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 13, 2020 (SOP Version 7).

pyruvate dehydrogenase E1-beta deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013580

Submitter: Orphanet

Clinical Genomic Database (CGD)

Pyruvate dehydrogensae E1-beta deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 15138885; 21914562

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDHB variants in ClinVar

9 Conditions Cataloged

Pyruvate dehydrogenase E1-beta deficiencyTotal: 332

Pyruvate dehydrogenase phosphatase deficiencyTotal: 39

not providedTotal: 29

Inborn genetic diseasesTotal: 26

not specifiedTotal: 25

Pyruvate dehydrogenase complex deficiencyTotal: 15

PDHB-related disorderTotal: 1

SeizureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000925.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	136 clinvar		143
missense	4 clinvar	8 clinvar	80 clinvar	4 clinvar		96
nonsense	3 clinvar	7 clinvar	2 clinvar			12
start loss	1 clinvar	1 clinvar	1 clinvar			3
frameshift	7 clinvar	9 clinvar				16
splice donor/acceptor (+/-2bp)	2 clinvar	6 clinvar	5 clinvar			13
Total	17	31	95	140	0	283

Highest pathogenic variant AF is 0.00023761785

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000925.4	RefSeq	NP_000916.2	10	MANE Select
ENST00000302746.11	Ensembl	ENSP00000307241.6	10	MANE Select
NM_001173468.2	RefSeq	NP_001166939.1	11	Standard
NM_001315536.2	RefSeq	NP_001302465.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pdhb	Danio rerio	Structure: amacrine cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

pdhb

Danio rerio

Structure: amacrine cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Citrate cycle (TCA cycle) - Homo sapiens (human)
Pyruvate metabolism - Homo sapiens (human)
Glycolysis / Gluconeogenesis - Homo sapiens (human)
Central carbon metabolism in cancer - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)

Biological Process

glucose metabolic process
acetyl-CoA biosynthetic process from pyruvate
tricarboxylic acid cycle
mitochondrial acetyl-CoA biosynthetic process from pyruvate

Molecular Function

pyruvate dehydrogenase activity
pyruvate dehydrogenase (acetyl-transferring) activity
protein binding
pyruvate dehydrogenase (NAD+) activity

Cellular Component

nucleus
nucleoplasm
mitochondrion
mitochondrial matrix
pyruvate dehydrogenase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302746
Coding exons: 10
Length: 6228
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.57	139	202	0.690	0.00000975	2339
Missense (PolyPhen)		37	86.725	0.42664		1048
Synonymous	-0.853	74	65.2	1.13	0.00000305	703
Loss of Function	2.98	5	19.0	0.263	8.77e-7	232

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle. {ECO:0000269|PubMed:17474719, ECO:0000269|PubMed:19081061}.;
Disease: DISEASE: Pyruvate dehydrogenase E1-beta deficiency (PDHBD) [MIM:614111]: An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. {ECO:0000269|PubMed:15138885}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.447

Intolerance Scores

LoFtool: 0.124
RVIS EVS: -0.41
RVIS percentile EVS: 26.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium